Pharmacological agents possessing the ability to block cellular transmembrane influx of calcium are capable of suppressing that portion of myocardial or smooth muscle contractility which is dependent upon extracellular calcium. These pharmacological agents, termed calcium antagonists, have been proven to be useful in the treatment of hypertension, cardiac arrhythmias, angina pectoris, cardiac myopathy and coronary artery vasospasm (a possible cause of sudden cardiac death syndrome). Can. J. Physiol. Pharmacol., 57, 433 (1979); Drugs, 15, 169 (1978); Acta Pharmacol. Toxicol., 43, suppl. 1,45 (1978).
In theory, calcium antagonists are thought to act by blocking calcium influx through discrete calcium channels (slow channels) in cell membranes. Various tissues exhibit relative differences in sensitivity toward the calcium blocking effect achieved by certain calcium antagonists, theoretically as a result of tissue specific differences in the calcium channels. Acta Pharmacol. Toxicol., 43, 5 (1978); loc cit. 291 (1978); Microvascular Res., 5, 73 (1973); Am. Rev. Pharmacol. Toxicol., 17, 149 (1977). Calcium channels of tissues which are most sensitive to calcium antagonist blockade are those which allow calcium influx only when the cell membranes are electrically depolarized. Alpha-adrenergic receptor-activated calcium channels are relatively unaffected by these agents. Circ. Res., 46, 246 (1980). This observation provides basis for evaluation of calcium antagonism.
The vascular smooth muscle tissue from the rabbit aorta can be made to contract when exposed to a depolarizing solution containing an elevated potassium ion concentration and normal amounts of calcium ions. Calcium antagonists added to the solution produce a dose dependent relaxation of the contracted rabbit aortic tissue. Normal contraction of the aortic tissue can then be induced in the presence of a calcium antagonist by subsequent addition of an alpha-adrenergic agonist, such as norepinephrine, to the solution. Eur. J. Pharmacol., 53, 281 (1979); Circ. Res., 46, 426 (1980); J. Exp. Pharmacol. Therap., 174, 500 (1970). The normal contraction produced by an alpha-adrenergic agonist after maximal smooth muscle relaxation has been induced by a calcium antagonist, serves to distinguish the calcium blocking effect of an agent from a nonspecific depressant effect on the muscle.